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US6861433B2 - Oxazolidinone photoaffinity probes - Google Patents

Oxazolidinone photoaffinity probes Download PDF

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Publication number
US6861433B2
US6861433B2 US09/738,022 US73802200A US6861433B2 US 6861433 B2 US6861433 B2 US 6861433B2 US 73802200 A US73802200 A US 73802200A US 6861433 B2 US6861433 B2 US 6861433B2
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mmol
compounds
compound
oxazolidinyl
oxo
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US20030073696A1 (en
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Lisa Marie Thomasco
Robert C. Gadwood
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Pharmacia and Upjohn Co
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Pharmacia and Upjohn Co
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Priority to US09/738,022 priority Critical patent/US6861433B2/en
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Priority to AU2002234016A priority patent/AU2002234016A1/en
Priority to CA002432739A priority patent/CA2432739A1/fr
Priority to EP01985023A priority patent/EP1368326A2/fr
Priority to JP2002549670A priority patent/JP2004520298A/ja
Priority to PCT/US2001/048063 priority patent/WO2002048139A2/fr
Assigned to PHARMACIA & UPJOHN COMPANY reassignment PHARMACIA & UPJOHN COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GADWOOD, ROBERT C., THOMASCO, LISA MARIE
Priority to US10/359,767 priority patent/US6875871B2/en
Priority to US10/359,766 priority patent/US6858635B2/en
Publication of US20030073696A1 publication Critical patent/US20030073696A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention is directed, in part, to novel photolabile oxazolidinones and preparation thereof.
  • novel compounds can be used as photoaffinity probes within sensitive bacteria including both gram-positive and gram-negative bacteria and mammalian cells.
  • antibiotic compounds have been developed and shown to be effective in inhibiting translation.
  • the antibiotics neomycin, thiostrepton, and hygromycin appear to inhibit translocation and occupation of the A site within a ribosome but have no effect on formation of the fMet-tRNA f Met /ribosome translation complex nor on the peptide-bond synthesis which occurs in the absence of elongation factor P.
  • Streptomycin which causes misreading and also inhibits A-site binding, interacts with two sites on the 16S rRNA of the 30S subunit. Lincomycin inhibits peptidyltransferase and occupation of the A-site.
  • Erythromycin inhibits peptidyltransferase and destabilizes the peptidyl-tRNA/ribosome/mRNA complex.
  • the present invention is directed, inter alia, to novel oxazolidinone compounds and use of oxazolidinone compounds as photoaffinity probes.
  • Compounds suspected of having antimicrobial and/or antibacterial activity can be used in intact cells and can be evaluated for a mechanism of action by using active and inactive enantiomers of oxazolidinone compounds as competitors for crosslinking to components within the cell.
  • the compounds and methods of the present invention allow one skilled in the art to elucidate the mechanism of action of antibacterial and/or antimicrobial agents that are suspected of inhibiting protein translation.
  • the present invention is directed to novel compounds that are useful and effective as photoaffinity probes useful for, inter alia, identification of the oxazolidinone binding site within gram-positive and gram-negative bacteria. These compounds can also be used for aiding in the determination of oxazolidinone binding sites within mammalian cells.
  • the compounds of the present invention comprise Formula I shown below. wherein X and Y are, independently, F, H or CH 3 ; R 1 is H or I; R 2 is H or OH; R 3 is H or C 1 -C 8 alkyl; L is a bond or —OCH 2 C( ⁇ O); and Q is wherein R 4 is H, CH 3 , CH 2 CH 3 or cyclopropyl; and Z is O or S; or a pharmaceutically acceptable salt thereof.
  • X and Y are, independently, F, H or CH 3 ; R 1 is H or I; R 2 is H or OH; and Q is wherein R 4 is H, CH 3 , CH 2 CH 3 or cyclopropyl; and Z is O or S; or a pharmaceutically acceptable salt thereof.
  • X and Y are, independently, F, H or CH 3 ;
  • R 5 is wherein R 6 is H, N 3 , halogen, NH 2 , OH, SH, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkyl, nitrile, carboxamide, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, or C 1 -C 4 alkoxycarbonyl; and
  • P is wherein Z is O or S;
  • R 7 is wherein R 1 is H or I; and R 2 is H or OH; or a pharmaceutically acceptable salt thereof.
  • Formula IV is wherein X and Y are, independently, F, H or CH 3 ; R 8 is H or I; R 9 is H or OH; R 10 is H or C 1 -C 8 alkyl; L is a bond or —OCH 2 C( ⁇ O); and Q is wherein R 11 is H, CH 3 , CH 2 CH 3 or cyclopropyl; and Z is O or S; or a pharmaceutically acceptable salt thereof.
  • Formula V is wherein X and Y are, independently, F, H or CH 3 ; R 12 is N 3 or wherein R 8 is H or I; R 9 is H or OH; and Q is wherein R 11 is H, CH 3 , CH 2 CH 3 or cyclopropyl; and Z is O or S; or a pharmaceutically acceptable salt thereof.
  • Formula VI is wherein X and Y are, independently, F, H or CH 3 ; R 13 is wherein R 14 is H, N 3 , halogen, NH 2 , OH, SH, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkyl, nitrile, carboxamide, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, or C 1 -C 4 alkoxycarbonyl; and P is wherein: Z is O or S; and R 15 is wherein R 8 is H or I; and R 9 is H or OH; or a pharmaceutically acceptable salt thereof.
  • cross-linking means the physical interaction between the photoaffinity probe and at least one component within a cell or from a cell or combinations thereof. Binding includes ionic, non-ionic, Hydrogen bonds, Van der Waals, hydrophobic interactions, etc.
  • the physical interaction, the binding can be either direct or indirect, indirect being through or because of another protein or compound. Direct binding refers to interactions that do not take place through or because of another protein or compound but instead are without other substantial chemical intermediates.
  • component within a cell means any protein, nucleic acid, lipid, etc. within a cell.
  • Components include, but are not limited to, the contents of the cytoplasm, nucleus, cell membrane, cell wall, and the like.
  • the term “competitor compound” means any identifiable chemical or molecule, small molecule, peptide, protein, sugar, natural or synthetic, that is suspected (such as a test compound) to potentially interact with or compete with the photoaffinity probe for cross-linking to a component within a cell or from a cell.
  • the term “contacting” means either direct or indirect, application of a photoaffinity compound or competitor compound within a cell, on or to a cell, or to components from a cell.
  • the competitor compound or photoaffinity compound can be present within a buffer, salt, solution, etc.
  • oxazolidinone means a compound of the class known as oxazolidinones, including the compounds described in U.S. Ser. Nos. 07/438,759, 07/553,795, 08/006,596, 07/882,407, 07/786,107, 07/831,213, 08/233,903, 08/119,279, 08/226,158, 08/155,988, 08/329,717, 07/909,387, 08/339,979, 08/384,278, 08/875,800, 07/880,432, 08/610,031, 08/332,822, 07/988,589, 08/003,778, 08/066,356, 08/438,705, 60/015,499, 60/003,149, 09/138,205, 09/138,209, 08/696,313, 60/012,316, 08/803,469, 60/003,838, 08/709,998, 60/008,554, 08/762,47
  • the present invention is directed to novel photoaffinity probes comprising Formula I, Formula II, or Formula III.
  • the preferred configuration at C-5 is (S). It will be appreciated by those skilled in the art that compounds of the present can have additional chiral centers and be isolated in optically active or racemic form.
  • the present invention encompasses any racemic, optically-active (such as enantiomers, diastereomers), tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention.
  • the present invention is also directed to compositions comprising photoaffinity probes which comprise Formula I, Formula II, or Formula III, or a mixture thereof.
  • Preferred compounds of this invention have one radioactive element which is either 3 H (T 3 ), 35 S, or 125 I. It is understood, however, that the Formulas include all isotopic forms of the compounds depicted.
  • compounds comprise Formula I, shown below. wherein X and Y are, independently, F, H or CH 3 in a variety of substitution patterns. Preferred compounds have one fluorine and one H.
  • R 1 is H or I.
  • R 2 is H or OH.
  • R 3 is H or C 1 -C 8 alkyl.
  • L is a bond or —OCH 2 C( ⁇ O).
  • Q is wherein R 4 is H, CH 3 , CH 2 CH 3 or cyclopropyl.
  • Z is O or S.
  • Compounds comprising Formula I also include pharmaceutically acceptable salts thereof.
  • Preferred compounds comprising Formula I have the following substituents: X is F, Y is H, R 3 is H, and R 4 is CH 3 . More preferably, compounds of Formula I include, but are not limited to, 2-[4-[4-[(5S)-5-[(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperazinyl]-2-oxoethyl-4-azido-2-hydroxy-5-iodo- 125 I-benzoate, N-[[(5S)-3-[4-[4-(4-Azido-2-hydroxy-5-iodo- 125 I-benzoyl)-1-piperazinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, 2-[4-[4-[(5S)-5-[(Acetylamino)methyl]-2-oxo-3
  • compounds comprise Formula II, shown below. wherein X and Y are, independently, F, H or CH 3 in a variety of substitution patterns. Preferred compounds have one fluorine and one H. R 1 is H or I. R 2 is H or OH. Q is wherein R 4 is H, CH 3 , CH 2 CH 3 or cyclopropyl. Z is O or S. Compounds comprising Formula II also include pharmaceutically acceptable salts thereof.
  • Preferred compounds comprising Formula II have the following substituents: X is F, Y is H, and R 4 is CH 3 . More preferably, compounds of Formula II include, but are not limited to, N-[[(5S)-3-(4′-Azido-2-fluoro[1,1′-biphenyl]-4-yl)-2-oxo-5-oxazolidinyl]methyl]-T 3 -acetamide, N-[[(5S)-3-(4′-Azido-2-fluoro-3′-iodo[1,1′-biphenyl]-4-yl)-2-oxo-5-oxazolidinyl]methyl]-T 3 -acetamide, N-[[(5S)-3-(4′-Azido-2-fluoro-3′-iodo[1,1′-biphenyl]-4-yl)-2-oxo-5-oxazolidinyl]methyl]ethane- 35 S
  • compounds comprise Formula III, shown below. wherein X and Y are, independently, F, H or CH 3 in a variety of substitution patterns. Preferred compounds have one fluorine and one H.
  • R 5 is wherein R 6 is H, N 3 , halogen, NH 2 , OH, SH, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkyl, nitrile, carboxamide, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, or C 1 -C 4 alkoxycarbonyl.
  • P is wherein Z is O or S.
  • R 7 is wherein R 1 is H or I.
  • R 2 is H or OH.
  • Compounds comprising Formula III also include pharmaceutically acceptable salts thereof.
  • Preferred compounds comprising Formula III have the following substituents: X is F, Y is H, and R 6 is H. More preferably, compounds of Formula III include, but are not limited to, (2E)-3-(4-azido-3-iodo- 125 I-phenyl)-N-[[(5S)-3-[3-fluoro-4-(4-pyridinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-propenamide, 4-azido-N-[[(5S)-3-[3-fluoro-4-(4-pyridinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-hydroxy-5-iodo- 125 I-benzamide, and N-(4-azidophenyl)-N′-[[(5S)-3-[3-fluoro-4-(4-pyridinyl)phenyl]-2-oxo-5-o
  • the present invention is also directed to methods of using a compound having Formula I, II, III, IV, V, or VI (shown above) as a photoaffinity probe.
  • a cell, or component(s) thereof is contacted with a photoaffinity probe comprising Formula I, II, III, IV, V, or VI.
  • the photoaffinity probe is radiolabled.
  • the photoaffinity probe is then exposed to light, preferably ultraviolet, in order to activate the photoaffinity probe.
  • Cross-linking of the photoaffinity probe is determined by methods well known to those skilled in the art such as, for example, by detecting the radiolabel.
  • Radiolabel such as 3 H, 125 I, or 35 S, for example, can be detected by a variety of autoradiography techniques well known to the skilled artisan.
  • the method further comprises contacting the cell or component(s) thereof with a competitor compound.
  • the ability of the competitor compound to interfere with cross-linking of the photoaffinity probe indicates the bioactivity of the competitor compound.
  • Cells of the present invention include, but are not limited to, gram positive bacterial pathogens, including, for example, Staphylococcus aureus; Staphylococcus epidermidis (A, B, C biotypes); Staphylococcus caseolyticus; Staphylococcus gallinarum; Staphylococcus haemolyticus; Staphylococcus hominis; Staphylococcus saprophyticus; Streptococcus agalactiae (group B); Streptococcus mutans/rattus; Streptococcus pneumoniae; Streptococcus pyogenes (group A); Streptococcus salivarius; Streptococcus sanguis; Streptococcus sobrinus; Actinomyces spps.; Arthrobacter histidinolovorans; Corynebacterium diptheriae; Clostridium difficle; Clostridium spps.; Enteroc
  • Cells also include, but are not limited to, gram negative bacterial pathogens, including, for example, Acinetobacter calcoaceticus; Acinetobacter haemolyticus; Aeromonas hydrophila; Bordetella pertussis; Bordetella parapertussis; Bordetella bronchiseptica; Bacteroides fragilis; Bartonella bacilliformis; Brucella abortus; Brucella melitensis; Campylobacter fetus; Campylobacter jejuni; Chlamydia pneumoniae; Chlamydia psittaci; Chlamydia trachomatis; Citrobacter freundii; Coxiella burnetti; Edwardsiella tarda; Edwardsiella hoshinae; Enterobacter aerogenes, Enterobacter cloacae (groups A and B); Escherichia coli (to include all pathogenic subtypes) Ehrlicia spp
  • paratyphi and S. typhi Salmonella subgroups 2, 3a, 3b, 4, and 5; Serratia marcesans; Serratia spps.; Shigella boydii; Shigella flexneri; Shigella dysenteriae; Shigella sonnei; Yersinia enterocolitica; Yersinia pestis; Yersinia pseudotuberculosis; Vibrio cholerae; Vibrio vulnificus ; and Vibrio parahaemolyticus.
  • Cells also include, but are not limited to, Mycobacterial species, including, for example, Mycobacterium tuberculosis; Mycobacterium avium ; and other Mycobacterium spps.
  • Mycobacterial species including, for example, Mycobacterium tuberculosis; Mycobacterium avium ; and other Mycobacterium spps.
  • Cells also include, but are not limited to, Mycoplasmas (or pleuropneumonia-like organisms), including, for example, Mycoplasma genitalium; Mycoplasma pneumoniae ; and other Mycoplasma spps.
  • Mycoplasmas or pleuropneumonia-like organisms
  • Mycoplasma genitalium including, for example, Mycoplasma genitalium; Mycoplasma pneumoniae ; and other Mycoplasma spps.
  • Cells also include, but are not limited to, Treponemataceae (spiral organisms) including, for example, Borrelia burgdorferi ; other Borrelia species; Leptospira spps.; Treponema pallidum.
  • Treponemataceae spiral organisms
  • Borrelia burgdorferi other Borrelia species
  • Leptospira spps. Treponema pallidum.
  • Non-radioactive compounds of Formulas I and IV are prepared by the methods described in Schemes A and B.
  • Scheme A coupling of a benzoic acid moiety (A 1 ) with an appropriate hydroxyacetyl piperazine fragment (A 2 ) leads to compounds A 3 of Formula I where L is —OCH 2 C( ⁇ O).
  • Coupling can be accomplished with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride or any other reagents familiar to ones skilled in the art.
  • Appropriate benzoic acid fragments can be made by procedures known in the literature. (Dupuis, Can. J. Chem., 1987, 65, 2450-2453; Shu, J.
  • Non-radioactive compounds of Formulas I and IV where L is a bond are prepared by the synthetic sequence shown in Scheme B.
  • An appropriate benzoic acid fragment (A 1 of Scheme A) is coupled with an appropriate piperazine (B 2 ) using 1,1-carbonyldiimidazole in tetrahydrofuran to give the desired compound (B 3 ).
  • B 2 1,1-carbonyldiimidazole in tetrahydrofuran
  • Other coupling methods known to those skilled in the art are also possible.
  • the piperazine fragment is made by methods known in the literature (Hutchinson, U.S. Pat. No. 5,700,799, which is incorporated herein by reference in its entirety; Barbachyn, U.S. Pat. No. 5,990,136; and Snyder, International Publication WO 00/10566-A1). Methods for incorporation of 125 I into compounds B 3 are shown in Schemes C and D.
  • Radioactive iodine is introduced into the compounds of Formulas I and IV by the methods shown in Schemes C and D.
  • Compounds C 2 of Formula I (where R 1 is OH and R 2 is 125 I) are prepared by reaction of compounds C 1 (prepared according to the methods of Schemes A and B) with Na 125 I and chloramine-T.
  • Non-radioactive compounds of Formulas II and V are prepared by the method shown in Scheme E.
  • the appropriate biphenyl nitro fragment (E 1 ) is reduced in the presence of hydrogen gas and a palladium catalyst to give the appropriate biphenyl aniline fragment (E 2 ).
  • Other reduction methods familiar to those skilled in the art may also be used.
  • Conversion to the azido moiety (E 3 ) can be accomplished via displacement of the appropriate diazonium salt with sodium azide using conditions familiar to those skilled in the art.
  • the appropriate nitro fragments (E 1 ) can be prepared by methods known in the literature (Barbachyn, U.S. Pat. No. 5,654,435, which is incorporated herein by reference in its entirety; Barbachyn U.S. Pat. No. 5,990,136; and Synder, International Publication WO 00/10566-A1) or by other methods familiar to those skilled in the art.
  • Introduction of radioactive elements into compounds of Formulas II and V are depicted in Schemes F, G,
  • Scheme F shows the procedure for incorporation of tritium into compounds of Formulas II and V where Q is oxazolidinone, Z is O, and R 4 is CH 3 .
  • Reaction of F 1 (prepared according to Scheme E) with 6N HCl and methanol affords the free amine F 2 .
  • Reaction of F 2 with tritiated sodium acetate and a coupling reagent affords the tritiated acetamide F 3 .
  • Suitable coupling reagents include O-benzotriazol-1-yl-N,N,N′,N′,tetramethyluronium hexafluorophosphate and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate.
  • Other acceptable coupling reagents are known by those skilled in the art.
  • tritiated acetic anhydride and a suitable base can be used in place of tritiated sodium acetate and a coupling reagent. Incorporation of tritium into compounds of Formulas II and V where Q is isoxazoline is carried out in similar fashion.
  • Scheme G shows the method for incorporation of 35 S into compounds of Formulas II and V where Q is oxazolidinone, Z is S, and R 4 is CH 3 .
  • Reaction of F 2 (from Scheme F) with ethyl 35 S-dithioacetate affords the 35 S-thioacetamide, G 2 .
  • Incorporation of 35 S into compounds of Formulas II and V where Q is isoxazoline is carried out in similar fashion.
  • Radioactive iodine can be introduced into compounds of Formulas II and V by the method shown in Scheme H.
  • Reaction of H 1 (prepared according to the route shown in Scheme E) with hexamethylditin affords the organostannane H 2 .
  • Reaction of H 2 with Na 125 I and chloramine-T affords the radioiodinated compound H 3 .
  • Scheme I illustrates a synthetic method for the preparation of non-radioactive compounds of Formulas III and VI where P is oxazolidinone, Z is O, and R 7 is optionally substituted azidophenyl or azidocinnamoyl.
  • Refluxing an appropriate acetamide fragment (I 1 ) in methanolic hydrochloric acid affords the free amine I 2 .
  • the acetamide fragments (I 1 ) are prepared by methods known in the literature (Barbachyn, U.S. Pat. No. 5,565,571, which is incorporated herein by reference in its entirety; Barbachyn, U.S. Pat. No. 5,990,136; and Synder, International Publication WO 00/10566-A1).
  • Coupling can be accomplished with EDC or other reagents familiar to ones skilled in the art.
  • Scheme L illustrates a synthetic method for the preparation of radioactive compounds of Formulas III and VI where P is oxazolidinone, Z is 35 S, and R 7 is optionally substituted azidoaniline.
  • An appropriate 35 S-isothiocyanate L 2 is reacted with the appropriate aminomethyl fragment I 2 (Scheme I) in refluxing THF to give the desired 35 S-thiourea, (L 3 ).
  • the required 35 S-isothiocyanate L 2 is prepared by reaction of an appropriate aniline with 35 S-thiophosgene.
  • Introduction of 35 S into compounds of Formulas III and VI where P is isoxazoline or isoxazolinone is carried out in similar fashion.
  • Step 1 To a stirred solution of (S)-N-[[3-[3-fluoro-4[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (515.8 mg, 1.31 mmol) in dimethylformamide (10 ml) and pyridine (1 ml) is added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (509.9 mg, 2.66 mmol) followed by 4-azidosalicylic acid (Dupuis, Can. J.
  • Step 2 All reagents are prepared in 0.1 N NaPO 4 buffer, pH 7.4 unless otherwise specified. Buffer (70 ⁇ l), chloramine-T (70 ⁇ l of a 1 mM stock solution), and the azido phenol of Step 1 (10 ⁇ l of a 50 ⁇ M stock solution in DMSO) are added to a 1.5 ml glass reaction vial. A rubber septum cap is crimped onto the reaction vial and a solution of 125 I 2 in sodium hydroxide (10 ⁇ l containing 1 mCi (Amersham #IMS 30) is added. The reaction is gently vortexed in the dark for 2 hours at room temperature then quenched with 10% solution of sodium bisulfite (100 ⁇ l).
  • the quenched reaction is diluted with buffer (800 ⁇ l) and transferred from the reaction vial with a 1 ml tuberculin syringe fitted with an 18 gauge needle.
  • the reaction volume (1 ml) is loaded onto a preconditioned C18 sep-pak cartridge (Millipore Corporation) and the unincorporated 125 I 2 is washed from the C18 resin with HPLC grade water containing 0.1% trifluoroacetic acid (20 ml).
  • Product is eluted using of 80% CH 3 CN/0.1 TFA (3 ml). The typical yield of iodinated product is approximately 30% of the total 125 I 2 added to the reaction.
  • Step 1 To a stirred suspension of (S)-N-[[3-[4-[3-fluoro-4-(1-piperazinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (498.0 mg, 1.3 mmol) in CH 2 Cl 2 (10 ml) is added diisopropylethylamine (0.70 ml, 4.0 mmol) followed by 4-azidosalicoyl chloride (342.6 mg, 1.7 mmol) in CH 2 Cl 2 (7 ml). The reaction mixture is stirred at room temperature for 18 hours and then is partitioned between CH 2 Cl 2 (50 ml) and H 2 O (10 ml). The phases are separated.
  • Step 2 Starting with the phenol prepared in Step 1, 125 I is introduced according to the procedure described in Step 2 of example 1.
  • Step 1 To a stirred solution of 4-azido-3-iodobenzoic acid (103.8 mg, 0.36 mmol, (Shu, J. of Labelled Compounds and Radiopharmaceuticals, 1996, 38, 227-237)) in dry THF (2.0 ml) is added 1,1-carbonyldiimidazole (58.2 mg, 0.36 mmol).
  • Step 2 To a stirred solution of the iodobenzoate prepared in Step 1 (62.7 mg, 0.094 mmol) and hexamethylditin (46.3 mg, 0.14 mmol) in dry THF (3 ml) is added dichlorobis(triphenylphosphine)palladium (II) (2.0 mg, 0.003 mmol). The reaction mixture is degassed and is heated at reflux for 3 hours. The reaction mixture is cooled and filtered through a pad of celite.
  • Step 3 To a stirred solution of the stannane prepared in Step 2 in dry acetonitrile is added a solution of 1M aqueous Na 125 I followed by chloramine-T hydrate. After stirring at room temperature for 30 minutes, the reaction mixture is quenched with saturated aqueous Na 2 S 2 O 3 and purified to give the radioiodinated material.
  • Step 1 To a stirred solution of 4-azido-3-iodobenzoic acid (272.0 mg, 0.94 mmol) in dry THF (4 ml) is added 1,1-carbonyldiimidazole (152.6 mg, 0.94 mmol). The reaction mixture is stirred at room temperature for 1 hour, then (S)-N-[[3-[4-[3-fluoro-4-(1-piperazinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (315.9 mg, 0.94 mmol) is added followed by DMF (2 ml). The reaction mixture is heated at reflux for 18 hours.
  • Step 2 To a stirred solution of the iodobenzamide prepared in Step 1 (82.4 mg, 0.13 mmol) and hexamethylditin (71.1 mg 0.22 mmol) in dry THF (6 ml) is added tetrakis(triphenylphosphine)palladium(0). The reaction mixture is degassed and heated at reflux for 12 hours. The cooled reaction mixture is filtered through a plug of celite and the filtrate is absorbed onto silica gel and purified on a Biotage 12M column with SIM using 2% CH 3 OH in 49% CH 2 Cl 2 and 49% EtOAC as the eluent to afford 28.2 mg (0.044 mmol, 34%) of the stannane.
  • 1 H-NMR (DMSO) ⁇ : 8.24, 7.50, 7.43, 7.35, 7.18, 7.17, 4.71, 4.08, 4.01, 3.70, 3.40, 2.99, 1.83, 0.32.
  • Step 3 To a stirred solution of the stannane prepared in Step 2 in dry acetonitrile is added a solution of 1M aqueous Na 125 I followed by chloramine-T hydrate. After stirring at room temperature for 30 minutes, the reaction mixture is quenched with saturated aqueous Na 2 S 2 O 3 and purified to give the desired radioiodinated material.
  • Step 1 To a stirred solution of 4-iodonitrobenzene (6.86 g, 27.5 mmol) in dry DMF (230 ml) is added bis(pinacolato)diboron (8.24 g, 32.4 mmol) followed by potassium acetate (8.68 g, 88.5 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (624.6 mg, 0.76 mmol). The reaction mixture is degassed and heated at 85° C. for 2 hours.
  • Step 2 A mixture of the nitrobiphenyl compound prepared in Step 1 (3.74 g, 10.0 mmol), 10% palladium on carbon in THF (100 ml), CH 3 OH (100 ml) and CH 2 Cl 2 (100 ml) is hydrogenated under a balloon of hydrogen for 18 hours. The reaction mixture is filtered through a pad of celite and the filtrate is concentrated to afford 2.50 g (7.3 mmol, 73%) of the desired aminobiphenyl.
  • 1 H-NMR (DMSO) ⁇ : 8.26, 7.45, 7.34, 7.23, 6.64, 5.28, 4.73, 4.14, 3.76, 3.42, 1.84.
  • Step 3 To a stirred solution of the aminobiphenyl prepared in Step 2 (508.93 mg, 1.48 mmol) in CH 3 OH (40 ml) and 1 M HCl (40 ml), cooled to 0° C. is added a 1.2 M aqueous NaNO 2 solution (1.48 ml, 1.78 mmol). The reaction mixture is stirred at 0° C. for 90 minutes, then sulfamic acid (143.5 mg, 1.48 mmol) is added followed by sodium azide (115.4 mg, 1.78 mmol) in H 2 O (1.5 ml). The reaction mixture is stirred at 0° C. for 45 minutes, then diluted with CH 2 Cl 2 (200 ml). The phases are separated.
  • Step 4 The azidobiphenyl prepared in Step 3 (102.4 mg, 0.27 mmol) in 6 N HCl (2 ml) and CH 3 OH (6 ml) is heated at reflux for 18 hours. The CH 3 OH is removed in vacuo and the solid precipitate is isolated by filtration and is washed successively with H 2 O (10 ml), ether (2 ⁇ 15 ml) then dried to afford 82.1 mg (0.23 mmol, 82%) of the desired amine hydrochloride.
  • Step 5 To a stirring solution of 0.57 mg (6.94 ⁇ mol, 250 mCi) of tritiated acetic acid sodium salt (American Radiolabeled Chemicals, lot no ARC 990519) in 1 ml of dry DMF and 2.71 mg (21 ⁇ mol) of diisopropylethylamine at room temperature, is added 6.94 ⁇ mol of 0.45M O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) in dry DMF. The solution instantly turned pale yellow and is stirred at room temperature for 10 minutes.
  • HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • the activated [ 3 H]acetic acid sodium salt was then added to a stirring solution of 2.73 mg (7.5 ⁇ mol) of the amine hydrochloride prepared in Step 4 in 2 ml of dry DMF.
  • the reaction is stirred at room temperature for 4.5 hours, then all solvents are removed by vacuum distillation at room temperature.
  • the crude reaction mixture is purified on a preparative TLC plate (Analtech Silica gel GF, 500 micron, 20 cm ⁇ 20 cm plate), eluted with 8% methanol in dichloromethane. The desired band is scrapped.
  • the product is eluted from the silica gel with 20% methanol in dichloromethane and filtered.
  • Step 1 To a stirred solution of the aniline prepared in Step 2 of Example 5 (284.9 mg, 0.83 mmol) in acetic acid (3 ml) is added iodine monochloride (134.5 mg, 0.83 mmol) in acetic acid (0.25 ml). The reaction mixture is stirred at room temperature for 1.5 hours. The reaction mixture is partitioned between EtOAc and aqueous Na 2 S 2 O 3 . The phases are separated. The aqueous phase is extracted with EtOAc (20 ml). The combined organic phases were dried (MgSO 4 ), filtered and concentrated.
  • Step 2 To a stirred solution of the iodoaniline prepared in Step 1 (47.2 mg, 0.10 mmol) in CH 3 OH (2 ml) and 1N HCl (2 ml) cooled to 0° C., is added a solution of NaNO 2 (8.5 mg, 0.12 mmol) in H 2 O (1 ml). The yellow reaction mixture is stirred at 0° C. for 30 minutes, then a solution of NaN 3 (8.0 mg, 0.12 mmol) in H 2 O (1 ml) is added. The reaction mixture is stirred at 0° C. for 1 hour, during which time a yellow precipitate formed.
  • Step 3 A mixture of 129 mg (0.26 mmol) of the iodoazidobiphenyl prepared in Step 2 (129.0 mg, 0.26 mmol), CH 3 OH (6 ml) and 1 N HCl (2 ml) are heated at reflux for 48 hours. The cooled reaction mixture is concentrated to afford quantitative yield the desired amine hydrochloride as a tan solid.
  • Step 4 To a solution of 5.1 mg (0.05 mmol, 25 mCi) of tritiated acetic anhydride (Amersham Batch B77, isotope #00-0316) is added 2 N PCl 3 in CH 2 Cl 2 (25 ⁇ l). The reaction mixture is left at room temperature for 5 hours with occasional mixing. To this mixture is added a solution of the amine hydrochloride prepared in Step 3 (47.7 mg, 0.104 mmol) in pyridine (0.25 ml) followed by DMAP (4.6 mg). After 30 minutes, the reaction mixture is partitioned between H 2 O and CH 2 Cl 2 . The phases are separated. The aqueous phase is extracted exhaustively with CH 2 Cl 2 and then concentrated. The residue is purified on silica gel (4 g) using 20% acetone in toluene as the eluent to afford 38.2 mg (0.077 mmol, 74%) of desired tritiated acetamide.
  • silica gel 4 g
  • Step 1 Methylmagnesium chloride in tetrahydrofuran (THF) is treated with 35 S labeled carbon disulfide at 40° C., followed by treatment with ethyl iodide. The reaction is stirred at 60° C. for 1.5 hours. After workup with water and ethyl ether, the desired ethyl 35 S-dithioacetate is obtained.
  • THF tetrahydrofuran
  • Step 2 The amine hydrochloride salt prepared in Step 3 of Example 6 and the ethyl [ 35 S]dithioacetate prepared in Step 1 are stirred in methylene chloride, methanol, and triethylamine to give the desired 35 S labeled thioamide.
  • Step 1 To a stirred solution of the iodobiphenyl prepared in Step 2 of Example 6 (56.2 mg, 0.11 mmol) and hexamethylditin (73.9 mg, 0.22 mmol) in toluene (5 ml) is added palladium (II) acetate (2.6 mg, 0.011 mmol) followed by triphenylphosphine (6.5 mg, 0.022 mmol). The reaction mixture is degassed and heated at 80° C. for 20 hours.
  • Step 2 To a stirred solution of the stannane prepared in Step 1 in dry CH 3 CN and pH 7 phosphate buffer is added chloramine-T followed by a solution of 1M aqueous Na 125 I. After 30 minutes, the reaction mixture is quenched with saturated aqueous Na 2 S 2 O 3 and purified to give the title compound.
  • Step 1 To a stirred solution of oxalyl chloride (0.10 mL, 1.2 mmol) in CH 2 Cl 2 (1.5 ml), cooled to ⁇ 78° C., is added dry DMSO (0.14 ml, 1.97 mmol). After 10 minutes, a solution of 4-azido-3-iodobenzyl alcohol (217.0 mg, 0.79 mmol (Shu, J. of Labeled Compounds and Radiopharmaceuticals, 1996, 38, 227-237)) in CH 2 Cl 2 (2.5 ml) is added. After 15 minutes, triethylamine (0.33 ml, 2.37 mmol) is added and the reaction mixture is allowed to warm to room temperature.
  • Step 2 To a stirred solution of the aldehyde prepared in Step 1 (190.0 mg, 0.69 mmol) in dry THF (1 ml) is added triethylphosphonoacetate (0.15 ml, 0.76 mmol) followed by lithium hydroxide monohydrate (32.1 mg, 0.76 mmol). The reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is poured into CH 2 Cl 2 (40 ml) and successively washed with H 2 O (20 ml), brine (20 ml), dried (MgSO 4 ), filtered and concentrated.
  • Step 3 To a stirred solution of the ester prepared in Step 2 (66.7 mg, 0.19 mmol) in CH 3 OH (2 ml) is added 1 N LiOH (0.19 ml, 0.19 mmol). The reaction mixture is heated at reflux for 12 hours. The cooled reaction mixture is concentrated and used immediately.
  • Step 5 The amine bis-hydrochloride (from Step 4) (68.2 mg, 0.19 mmol), the lithium carboxylate prepared in Step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (72.8 mg, 0.38 mmol) and 1-hydroxybenzotriazole hydrate (30.8 mg, 0.23 mmol) are dissolved in pyridine (2 ml) and stirred at room temperature for 72 hours. The reaction mixture is concentrated. The residue is dissolved in CH 2 Cl 2 (40 ml) and washed with H 2 O (20 ml), brine (20 ml), dried (MgSO 4 ), filtered and concentrated.
  • Step 6 To a stirred solution of the iodocinnamide prepared in Step 4 and hexamethylditin in dry THF is added tetrakis(triphenylphosphine)palladium(0). The reaction mixture is degassed and heated at reflux for 12 hours. The cooled reaction mixture is filtered through a plug of celite and the filtrate is absorbed onto silica gel and purified on a Biotage 12M column with SIM to afford the stannane.
  • Step 7 To a stirred solution of the stannane prepared in Step 5 in dry acetonitrile is added a solution of 1M aqueous Na 125 I followed by chloramine-T hydrate. After stirring at room temperature for 30 minutes, the reaction mixture is quenched with saturated aqueous Na 2 S 2 O 3 and purified to give the desired radioiodinated material.
  • Step 1 To a stirred suspension of the amine bis-hydrochloride salt prepared in Step 4 of Example 9 (172.4 mg, 0.48 mmol) in pyridine (4 ml) and CH 2 Cl 2 (1 ml) is added 4-azidosalicylic acid (128.9 mg 0.72 mmol) followed by added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (184.0 mg, 0.96 mmol) and 1-hydroxybenzotriazole hydrate (77.8 mg, 0.58 mmol). The reaction mixture is stirred at room temperature for 72 hours then concentrated.
  • Step 2 Starting with the phenol prepared in Step 1, 125 I is introduced according to the procedure described in Step 2 of Example 1.

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CA002432739A CA2432739A1 (fr) 2000-12-15 2001-12-14 Sonde de photo-affinite a base d'oxazolidinone
EP01985023A EP1368326A2 (fr) 2000-12-15 2001-12-14 Sonde de photo-affinite a base d'oxazolidinone
JP2002549670A JP2004520298A (ja) 2000-12-15 2001-12-14 オキサゾリジノン系の光親和性プローブ
AU2002234016A AU2002234016A1 (en) 2000-12-15 2001-12-14 Oxazolidinone photoaffinity probes
PCT/US2001/048063 WO2002048139A2 (fr) 2000-12-15 2001-12-14 Sonde de photo-affinite a base d'oxazolidinone
US10/359,767 US6875871B2 (en) 2000-12-15 2003-02-06 Oxazolidinone photoaffinity probes
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WO2005051933A1 (fr) * 2003-11-28 2005-06-09 Ranbaxy Laboratories Limited Procede ameliore de synthese d'ester test-butylique d'acide 4-(4-benzyloxy-carbonylamino-2-fluorophenyl)-piperazine-1-carboxylique, compose intermediaire cle de la preparation d'agents antimicrobiens a l'oxazolidinone, et composes ainsi prepares

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WO1993009103A1 (fr) 1991-11-01 1993-05-13 The Upjohn Company Aryl- et heteroarylphenyloxazolidinones substituees, utilisees comme agents antibacteriens
WO1995014684A1 (fr) 1993-11-22 1995-06-01 The Upjohn Company Esters d'hydroxyacetyl-piperazine-phenyl-oxazolidinones substituees
US5910504A (en) 1995-02-03 1999-06-08 Pharmacia & Upjohn Hetero-aromatic ring substituted phenyloxazolidinone antimicrobials
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WO2000010566A1 (fr) 1998-08-24 2000-03-02 Bristol-Myers Squibb Company Nouveaux agents antibacteriens a base d'isoxazolinone
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WO1995014684A1 (fr) 1993-11-22 1995-06-01 The Upjohn Company Esters d'hydroxyacetyl-piperazine-phenyl-oxazolidinones substituees
US5652238A (en) 1993-11-22 1997-07-29 Pharmacia & Upjohn Company Esters of substituted-hydroxyacetyl piperazine phenyl oxazolidinones
US5910504A (en) 1995-02-03 1999-06-08 Pharmacia & Upjohn Hetero-aromatic ring substituted phenyloxazolidinone antimicrobials
WO1999041244A1 (fr) 1998-02-13 1999-08-19 Pharmacia & Upjohn Company Derives d'isoxazoline aminophenyle substitues utilises comme agents antimicrobiens
WO2000010566A1 (fr) 1998-08-24 2000-03-02 Bristol-Myers Squibb Company Nouveaux agents antibacteriens a base d'isoxazolinone
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